Novel Macrolide Antibiotic Nafithromycin for Tackling Emerging Resistance in Respiratory Pathogens Encountered in India.

Nafithromycin (WCK 4873), is India's first approved macrolide antibiotic by DCGI(Drug Controller General of India), represents a significant advancement in combating antimicrobial resistance (AMR) and multidrug-resistant (MDR) pathogens. After three decades of research and development, supported by BIRAC, Wockhardt Ltd. successfully developed this innovative lactone- ketolide antibiotic which demonstrates superior efficacy against respiratory pathogens, particularly drug-resistant Streptococcus pneumoniae. Its unique structural modifications at the C-3 position and enhanced side chain configurations improve its pharmacological profile compared to previous generation macrolides. Nafithromycin binds to both domains II and V of 23 s rRna, thereby circumventing the resistance mechanisms which impacts older macrolide due to their single target binding. Owing to dual binding of nafithromycin, it is more potent than the older macrolides. Additionally, nafithromycin exhibits immunomodulatory effects in acute lung injury models, suggesting potential therapeutic benefits beyond its antimicrobial activity. Moreover, Phase I and II trials demonstrate its safety and tolerability, with minimal drug-drug interactions due to reduced CYP3A4/5 inhibition. Phase III results show that nafithromycin is effective against a wide variety of respiratory infections as well as intracellular atypical pathogens which can be difficult to treat other ways. No significant AEs were encountered. In this comprehensive review, the adverse effects of other antibiotics are examined, along with the benefits of nafithromycin over other medications, its development, mechanism of action, structure-activity relationships, clinical efficacy, drug delivery strategies via various routes to overcome antimicrobial resistance, strategies to combat antimicrobial resistance, and future perspectives in addressing the global antimicrobial resistance challenges.